US6497883B1 - Porcine circovirus recombinant poxvirus vaccine - Google Patents

Porcine circovirus recombinant poxvirus vaccine Download PDF

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US6497883B1
US6497883B1 US09/583,545 US58354500A US6497883B1 US 6497883 B1 US6497883 B1 US 6497883B1 US 58354500 A US58354500 A US 58354500A US 6497883 B1 US6497883 B1 US 6497883B1
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recombinant
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Michel Bublot
Jennifer M. Perez
Catherine E. Charreyre
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Boehringer Ingelheim Animal Health France SAS
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Merial SAS
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Priority to US09/583,545 priority Critical patent/US6497883B1/en
Application filed by Merial SAS filed Critical Merial SAS
Priority to AT00938971T priority patent/ATE476510T1/de
Priority to EP00938971A priority patent/EP1185660B1/fr
Priority to DK00938971.9T priority patent/DK1185660T3/da
Priority to ES08005549.4T priority patent/ES2560513T3/es
Priority to DE60044778T priority patent/DE60044778D1/de
Priority to CA2376600A priority patent/CA2376600C/fr
Priority to PL352201A priority patent/PL205032B1/pl
Priority to PT80055494T priority patent/PT1975235E/pt
Priority to DK08005549.4T priority patent/DK1975235T3/en
Priority to MXPA01012723A priority patent/MXPA01012723A/es
Priority to HU0201689A priority patent/HU229051B1/hu
Priority to EP08005549.4A priority patent/EP1975235B1/fr
Priority to AU54189/00A priority patent/AU778520B2/en
Priority to BR0011737-4A priority patent/BR0011737A/pt
Priority to BRPI0011737-4A priority patent/BRPI0011737B1/pt
Priority to PT00938971T priority patent/PT1185660E/pt
Priority to KR1020017015883A priority patent/KR100837724B1/ko
Priority to PCT/IB2000/000882 priority patent/WO2000077216A2/fr
Priority to JP2001503659A priority patent/JP4859316B2/ja
Priority to CNB00810560XA priority patent/CN1195854C/zh
Assigned to MERIAL reassignment MERIAL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHARREYRE, CATHERINE E., PEREZ, JENNIFER, BUBLOT, MICHEL
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Priority to CY20101100958T priority patent/CY1116483T1/el
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5256—Virus expressing foreign proteins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/24011—Poxviridae
    • C12N2710/24041—Use of virus, viral particle or viral elements as a vector
    • C12N2710/24043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/10011—Circoviridae
    • C12N2750/10022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to vectors, such as recombinant vectors; for instance, recombinant viruses, such as poxviruses, e.g., modified poxviruses and to methods of making and using the same.
  • the invention relates to recombinant avipox viruses, such as canarypox viruses, e.g., ALVAC.
  • the invention further relates to such vectors, e.g., poxviruses, that express gene products, e.g., antigen(s), ORF(s), and/or epitope(s) of interest therefrom, of porcine circovirus 2 (PCV2); to immunological compositions or vaccines.
  • PCV2 porcine circovirus 2
  • the invention yet further relates to such vectors, e.g., poxviruses, that induce an immune response directed to or against PCV2 gene products and/or PCV2; and, to advantageously, such compositions that are immunological, immunogenic or vaccine compositions and/or confer protective immunity against infection by PCV2.
  • the invention yet further relates to the uses of and methods for making and using such vectors and compositions, as well as intermediates thereof, and said intermediates.
  • the invention relates to the products therefrom, e.g., from the uses and methods involving the inventive recombinant or poxvirus, such as antibodies from expression.
  • PMWS Postweaning multisystemic wasting syndrome
  • Circoviruses are single stranded circular DNA viruses found in a range of animal and plant species. Porcine circovirus was originally isolated as a contaminant from a continuous pig kidney cell line. The cell culture isolate has been designated PK-15 (Meehan et al., 1997). More recently, porcine circovirus obtained from pigs with PMWS has been compared to PK-15. Such viruses differ substantially from PK-15 at the nucleotide and protein sequence level, and have been designated PCV2 (Meehan et al., 1998; Hamel et al., 1998).
  • ORFs open reading frames
  • ORF2 (Meehan et al., 1998; corresponding to COL13 in the French patent application 98 03707), comprising nt 1381-1768 joined to 1-314 (GenBank accession number AF055392), may encode a protein with a predicted molecular weight of 27.8 kD.
  • ORF3 (Meehan et al., 1998; corresponding to COL7 in the French patent application 98 03707), comprising nt 1018-704 (GenBank accession number AF055392), may encode a protein with a predicted molecular weight of 11.9 kD.
  • ORF4 (Meehan et al., 1998; corresponding to COL10 in the French patent application 98 03707), comprising nt 912-733 (GenBank accession number AF055392), may encode a protein with a predicted molecular weight of 6.5 kD.
  • ORF1 of PCV2 is highly homologous (86% identity) to the ORF1 of the PK-15 isolate (Meehan et al., 1998).
  • the ORF1 protein of PK-15 has been partially characterized (Meehan et al., 1997; Mankertz et al., 1998a). It is known to be essential for virus replication, and is probably involved in the viral DNA replication.
  • Vaccinia virus has been used successfully to immunize against smallpox, culminating in the worldwide eradication of smallpox in 1980. With the eradication of smallpox, a new role for poxviruses became important, that of a genetically engineered vector for the expression of foreign genes (Panicali and Paoletti, 1982; Paoletti et al., 1984). Genes encoding heterologous antigens have been expressed in vaccinia, often resulting in protective immunity against challenge by the corresponding pathogen (reviewed in Tartaglia et al., 1990). A highly attenuated strain of vaccines, designated MVA, has also been used as a vector for poxvirus-based vaccines. Use of MVA is described in U.S. Pat. No. 5,185,146.
  • Fowlpox virus is the prototypic virus of the Avipox genus of the Poxvirus family. The virus causes an economically important disease of poultry which has been well controlled since the 1920's by the use of live attenuated vaccines.
  • avipox viruses Replication of the avipox viruses is limited to avian species (Matthews, 1982) and there are no reports in the literature of avipoxvirus causing a productive infection in any non-avian species including man. This host restriction provides an inherent safety barrier to transmission of the virus to other species and makes use of avipoxvirus based vaccine vectors in veterinary and human applications an attractive proposition.
  • FPV has been used advantageously as a vector expressing antigens from poultry pathogens.
  • the hemagglutinin protein of a virulent avian influenza virus was expressed in an FPV recombinant (Taylor et al., 1988c).
  • an immune response was induced which was protective against either a homologous or a heterologous virulent influenza virus challenge (Taylor et al., 1988c).
  • FPV recombinants expressing the surface glycoproteins of Newcastle Disease Virus have also been developed (Taylor et al., 1990; Edbauer et al., 1990).
  • Attenuated poxvirus vectors have been prepared by genetic modifications of wild type strains of virus.
  • the NYVAC vector derived by deletion of specific virulence and host-range genes from the Copenhagen strain of vaccinia (Tartaglia et al., 1992) has proven useful as a recombinant vector in eliciting a protective immune response against an expressed foreign antigen.
  • ALVAC derived from canarypox virus
  • ALVAC canarypox virus
  • ALVAC does not productively replicate in non-avian hosts, a characteristic thought to improve its safety profile (Taylor et al., 1991 & 1992).
  • Both ALVAC and NYVAC are BSL-1 vectors.
  • Recombinant poxviruses can be constructed in two steps known in the art and analogous to the methods for creating synthetic recombinants of poxviruses such as the vaccinia virus and avipox virus described in U.S. Pat. Nos. 4,769,330; 4,722,848; 4,603,112; 5,110,587; 5,174,993; 5,494,807; and 5,505,941, the disclosures of which are incorporated herein by reference.
  • PCV2 recombinant poxvirus and of compositions and products therefrom particularly ALVAC based PCV2 recombinants and compositions and products therefrom, especially such recombinants containing ORFs 1 and/or 2 of PCV2, and compositions and products therefrom would be a highly desirable advance over the current state of technology.
  • the present invention relates to an antigenic, immunological, immunogenic, or vaccine composition or a therapeutic composition for inducing an antigenic, immunogenic or immunological response in a host animal inoculated with the composition.
  • the composition advantageously includes a carrier or diluent and a recombinant virus, such as a recombinant poxvirus.
  • the recombinant virus or poxvirus contains and expresses an exogenous nucleic acid molecule encoding an ORF, antigen, immunogen, or epitope of interest from PCV2, or a protein that elicits an immunological response against PCV2 or conditions caused by PCV2, such as PMWS.
  • the recombinant virus can be a modified recombinant virus or poxvirus; for example, such a virus or poxvirus that has inactivated therein virus-encoded genetic functions, e.g., nonessential virus-encoded genetic functions, so that the recombinant virus has attenuated virulence and enhanced safety.
  • the invention further provides the viruses used in the composition, as well as methods for making and uses of the composition and virus.
  • the virus used in the composition according to the present invention is advantageously a poxvirus, particularly a vaccinia virus or an avipox virus, such as fowlpox virus or canarypox virus and more advantageously, ALVAC.
  • the modified recombinant virus can include, e.g., within a non-essential region of the virus genome, a heterologous DNA sequence which encodes an antigenic protein, e.g., derived from PCV2 ORFs, e.g., PCV2 ORF 1 and/or 2.
  • the present invention relates to an immunogenic composition containing a modified recombinant virus having inactivated nonessential virus-encoded genetic functions so that the recombinant virus has attenuated virulence and enhanced safety.
  • the modified recombinant virus includes, e.g., within a non-essential region of the virus genome, a heterologous DNA sequence which encodes an antigenic protein (e.g., derived from PCV2 ORFs, especially ORFS 1 and/or 2) wherein the composition, when administered to a host, is capable of inducing an immunological response specific to the antigen.
  • the present invention relates to a modified recombinant virus having nonessential virus-encoded genetic functions inactivated therein so that the virus has attenuated virulence, and wherein the modified recombinant virus further contains DNA from a heterologous source, e.g., in a nonessential region of the virus genome.
  • the DNA can code for PCV2 genes such as any or all of PCV2 ORF1, ORF2, ORF3, or ORF4 (Meehan et al., 1998), or epitope(s) of interest therefrom.
  • the genetic functions can be inactivated by deleting an open reading frame encoding a virulence factor or by utilizing naturally host-restricted viruses.
  • the virus used according to the present invention is advantageously a poxvirus, e.g., a vaccinia virus or an avipox virus, such as fowlpox virus or canarypox virus.
  • the open reading frame that is deleted from the poxvirus or virus geneome is selected from the group consisting of J2R, B13R+B14R, A26L, A56R, C7L ⁇ K1L, and I4L (by the terminology reported in Goebel et al., 1990); and, the combination thereof.
  • the open reading frame comprises a thymidine kinase gene, a hemorrhagic region, an A type inclusion body region, a hemagglutinin gene, a host range gene region or a large subunit, ribonucleotide reductase; or, the combination thereof.
  • a suitable modified Copenhagen strain of vaccinia virus is identified as NYVAC (Tartaglia et al., 1992), or a vaccinia virus from which has been deleted J2R, B13R+B14R, A26L, A56R, C7L ⁇ K11 and 14L or a thymidine kinase gene, a hemorrhagic region, an A type inclusion body region, a hemagglutinin gene, a host range region, and a large subunit, ribonucleotide reductase (See also U.S. Pat. Nos. 5,364,773, 5,494,807, and 5,762,938, with respect to NYVAC and vectors having additional deletions or inactivations from those of NYVAC that are also useful in the practice of this invention).
  • the poxvirus vector is an ALVAC or, a canarypox virus which was attenuated, for instance, through more than 200 serial passages on chick embryo fibroblasts (Rentschler vaccine strain), a master seed therefrom was subjected to four successive plague purifications under agar from which a plague clone was amplified through five additional passages.
  • ALVAC chick embryo fibroblasts
  • TROVAC an attenuated fowlpox virus useful in the practice of this invention
  • vectors useful with porcine hosts can include a poxvirus, including a vaccinia virus, an avipox virus, a canarypox virus, and a swinepox virus), as well as with respect to terms used and teachings herein such as “immunogenic composition”, “immunological composition”, “vaccine”, and “epitope of interest”, and dosages, routes of administration, formulations, adjuvants, and uses for recombinant viruses and expression products therefrom).
  • poxvirus including a vaccinia virus, an avipox virus, a canarypox virus, and a swinepox virus
  • the invention in yet a further aspect relates to the product of expression of the inventive recombinant poxvirus and uses therefor, such as to form antigenic, immunological or vaccine compositions for treatment, prevention, diagnosis or testing; and, to DNA from the recombinant poxvirus which is useful in constructing DNA probes and PCR primers.
  • FIG. 1 shows the nucleotide sequence of a 3.7 kilobase pair fragment of ALVAC DNA containing the C6 open reading frame.
  • FIG. 2 shows the map of pJP102 donor plasmid.
  • FIG. 3 shows the nucleotide sequence of the 2.5 kilobase pair fragment from pJP 102 donor plasmid from the KpnI (position 653) to the Sacl (position 3166) restriction sites.
  • FIG. 4 shows the map of pJP105 donor plasmid.
  • FIG. 5 shows the map of pJP107 donor plasmid.
  • FIG. 6 shows the nucleotide sequence of the 3.6 kilobase pair fragment from pJP107 donor plasmid from the KpnI (position 653) to the Sacl (position 4255) restriction sites.
  • the present invention relates to a recombinant virus, such as a recombinant poxvirus, containing therein a DNA sequence from PCV2, e.g., in a non-essential region of the poxvirus genome.
  • the poxvirus is advantageously an avipox virus, such as fowlpox virus, especially an attenuated fowlpox virus, or a canarypox virus, especially an attenuated canarypox virus, such as ALVAC.
  • the recombinant poxvirus expresses gene products of the foreign PCV2 gene.
  • Specific ORFs of PCV2 are inserted into the poxvirus vector, and the resulting recombinant poxvirus is used to infect an animal. Expression in the animal of PCV2 gene products results in an immune response in the animal to PCV2.
  • the recombinant poxvirus of the present invention may be used in an immunological composition or vaccine to provide a means to induce an immune response which may, but need not be, protective.
  • compositions of the invention such as immunological, antigenic or vaccine compositions or therapeutic compositions
  • parenteral route intradermal, intramuscular or subcutaneous.
  • Such an administration enables a systemic immune response, or humoral or cell-mediated responses.
  • inventive poxvirus-PCV2 recombinants, antigenic, immunological or vaccine poxvirus-PCV2 compositions or therapeutic compositions can be prepared in accordance with standard techniques well known to those skilled in the pharmaceutical or veterinary art. Such compositions can be administered in dosages and by techniques well known to those skilled in the medical or veterinary arts taking into consideration such factors as the age, sex, weight, species and condition of the particular patient, and the route of administration.
  • the compositions can be administered alone, or can be co-administered or sequentially administered with compositions, e.g., with “other” immunological, antigenic or vaccine or therapeutic compositions thereby providing multivalent or “cocktail” or combination compositions of the invention and methods employing them.
  • ingredients and manner (sequential or co-administration) of administration, as well as dosages can be determined taking into consideration such factors as the age, sex, weight, species and condition of the particular patient, and, the route of administration.
  • compositions of the invention include liquid preparations for orifice, e.g., oral, nasal, anal, vaginal, peroral, intragastric, etc., administration such as suspensions, syrups or elixirs; and, preparations for parenteral, subcutaneous, intradermal, intramuscular or intravenous administration (e.g., injectable administration) such as sterile suspensions or emulsions.
  • parenteral, subcutaneous, intradermal, intramuscular or intravenous administration e.g., injectable administration
  • sterile suspensions or emulsions e.g., injectable administration
  • the recombinant poxvirus or antigens may be in admixture with a suitable carrier, diluent, or excipient such as sterile water, physiological saline, glucose or the like.
  • the compositions can also be lyophilized.
  • compositions can contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, adjuvants, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, adjuvants, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired.
  • Standard texts such as “REMINGTON'S PHARMACEUTICAL SCIENCE”, 17th edition, 1985, incorporated herein by reference, may be consulted to prepare suitable preparations, without undue experimentation. Suitable dosages can also be based upon the Examples below.
  • compositions can contain at least one adjuvant compound chosen from the polymers of acrylic or methacrylic acid and the copolymers of maleic anhydride and alkenyl derivative.
  • the preferred adjuvant compounds are the polymers of acrylic or methacrylic acid which are cross-linked, especially with polyalkenyl ethers of sugars or polyalcohols. These compounds are known by the term carbomer (Phameuropa Vol. 8, No. 2, June 1996). Persons skilled in the art can also refer to U.S. Pat. No. 2,909,462 (incorporated herein by reference) which describes such acrylic polymers cross-linked with a polyhydroxylated compound having at least 3 hydroxyl groups, preferably not more than 8, the hydrogen atoms of at least three hydroxyls being replaced by unsaturated aliphatic radicals having at least 2 carbon atoms.
  • the preferred radicals are those containing from 2 to 4 carbon atoms, e.g.
  • the unsaturated radicals may themselves contain other substituents, such as methyl.
  • the products sold under the name Carbopol® (BF Goodrich, Ohio, USA) are particularly appropriate. They are cross-linked with an allyl sucrose or with allyl pentaerythritol. Among then, there may be mentioned Carbopol® 974P, 934P and 971P.
  • copolymers of maleic anhydride and alkenyl derivative the copolymers EMA® (Monsanto) which are copolymers of maleic anhydride and ethylene, linear or cross-linked, for example cross-linked with divinyl ether, are preferred.
  • EMA® Monsanto
  • the polymers of acrylic or methacrylic acid and the copolymers EMA® are preferably formed of basic units of the following formula:
  • R 1 and R 2 which are identical or different, represent H or CH 3
  • a solution of adjuvant according to the invention is prepared in distilled water, preferably in the presence of sodium chloride, the solution obtained being at acidic pH.
  • This stock solution is diluted by adding it to the desired quantity (for obtaining the desired final concentration), or a substantial part thereof, of water charged with NaCl, preferably physiological saline (NaCL 9 g/l) all at once in several portions with concomitant or subsequent neutralization (pH 7.3 to 7.4), preferably with NaOH.
  • NaCl physiological saline
  • This solution at physiological pH will be used as it is for mixing with the vaccine, which may be especially stored in freeze-dried, liquid or frozen form.
  • the polymer concentration in the final vaccine composition will be 0.01% to 2% w/v, more particularly 0.06 to 1% w/v, preferably 0.1 to 0.6% w/v.
  • the immunological compositions according to the invention may be associated to at least one live attenuated, inactivated, or sub-unit vaccine, or recombinant vaccine (e.g. poxvirus as vector or DNA plasmid) expressing at least one immunogen from another pig pathogen.
  • the invention encompasses vectors encoding and expressing equivalent nucleotide sequences, that is to say the sequences which change neither the functionality or the strain specificity (say strain of type 1 and strain of type 2) of the gene considered or those of the polypeptides encoded by this gene.
  • the sequences differing through the degeneracy of the code are, of course, included.
  • PCV-2 sequences used in the examples are derived from Meehan et al. (Strain Imp.1010; ORF1 nucleotides 398-1342; ORF2 nucleotides 1381-314; and correspond respectively to ORF4 and ORF13 in U.S. application Ser. No. 09/161,092 of Sep. 25 1998 and to COL4 and COL13 in WO-A-9918214).
  • Other PCV-2 strains and their sequences have been published in WO-A-9918214 and are called Imp1008, Imp999, Imp1011-48285 and Imp1011-48121, as well as in A.L. Hamel et al. J. Virol.
  • the invention also encompasses the equivalent sequences to those used herein and in documents cited herein; for instance, sequences that are capable of hybridizing to the nucleotide sequence under high stringency conditions (see, e.g., Sambrook et al. (1989).
  • sequences that are capable of hybridizing to the nucleotide sequence under high stringency conditions see, e.g., Sambrook et al. (1989).
  • equivalent sequences there may also be mentioned the gene fragments conserving the immunogenicity of the complete sequence, e.g., an epitope of interest.
  • the homology of the whole genome between PCV types 1 and 2 is about 75%. For ORF1, it is about 86%, and for ORF2, about 66%. On the contrary, homologies between genomes and between ORFs within type 2 are generally above 95%.
  • equivalent sequences useful in the practice of this present invention are those sequences having an homology equal or greater than 88%, advantageously 90% or greater, preferably 92% or 95% or greater with ORF1 of strain Imp1010, and for ORF2, are those sequences having an homology equal or greater than 80%, advantageously 85% or greater, preferably 90% or 95% or greater with ORF2 of strain Imp1010.
  • ORF1 and ORF2 according to Meehan 1998 has the potential to encode proteins with predicted molecular weights of 37.7 kD and 27.8 kD respectively.
  • ORF3 and ORF4 (according to Meehan et al. 1998, correspond to ORF7 and ORF10 respectively in WO-A-9918214) has the potential to encode proteins with predicted molecular weights of 11.9 and 6.5 kD respectively.
  • the sequence of these ORFs is also available in Genbank AF 055392. They can also be incorporated in plasmids and be used in accordance with the invention alone or in combination, e .g. with ORF1 and/or ORF2.
  • ORFs 1-3 and 5, 6, 8-9, 11-12 disclosed in U.S. application Ser. No. 09/161,092 of Sep. 25 1998 (COLs 1-3 and 5, 6, 8-9, 11-12 in WO-A-9918214), or region(s) thereof encoding an antigen or epitope of interest, may be used in the practice of this invention, e.g., alone or in combination or otherwise with each other or with the ORFs 1 and 2 or region(s) thereof encoding antigen(s) or epitope(s).
  • This invention also encompasses the use of equivalent sequences; for instance, from ORFs of various PCV-2 strains cited herein. For homology, one can determine that there are equivalent sequences which come from a PCV strain having an ORF2 and/or an ORF1 which have an homology as defined above with the corresponding ORF of strain 1010.
  • an equivalent sequence has homology thereto that is advantageously, for instance, equal or greater than 80%, for example 85% or greater, preferably 90% or 95% or greater with ORF3 of strain ImplO10.
  • an equivalent sequence has homology that is equal or greater than 86%, advantageously 90% or greater, preferably than 95% or greater with ORF4 of strain Imp1010.
  • Nucleotide sequence homology can be determined using the “Align” program of Myers and Miller, (“Optimal Alignments in Linear Space”, CABIOS 4, 11-17, 1988, incorporated herein by reference) and available at NCBI.
  • the term “homology” or “identity”, for instance, with respect to a nucleotide or amino acid sequence can indicate a quantitative measure of homology between two sequences.
  • the percent sequence homology can be calculated as (N ref -N dif )* 100N ref , wherein N dif is the total number of non-identical residues in the two sequences when aligned and wherein N ref is the number of residues in one of the sequences.
  • “homology” or “identity” with respect to sequences can refer to the number of positions with identical nucleotides or amino acids divided by the number of nucleotides or amino acids in the shorter of the two sequences wherein alignment of the two sequences can be determined in accordance with the Wilbur and Lipman algorithm (Wilbur and Lipman, 1983 PNAS USA 80:726, incorporated herein by reference), for instance, using a window size of 20 nucleotides, a word length of 4 nucleotides, and a gap penalty of 4, and computer-assisted analysis and interpretation of the sequence data including alignment can be conveniently performed using commercially available programs (e.g., IntelligeneticsTMSuite, Intelligenetics Inc. CA).
  • thymidine (T) in the DNA sequence is considered equal to uracil (U) in the RNA sequence.
  • RNA sequences within the scope of the invention can be derived from DNA sequences, by thymidine (T) in the DNA sequence being considered equal to uracil (U) in RNA sequences.
  • amino acid sequence similarity or identity or homology can be determined using the BlastP program (Altschul et al., Nucl. Acids Res. 25, 3389-3402, incorporated herein by reference) and available at NCBI.
  • the following references (each incorporated herein by reference) provide algorithms for comparing the relative identity or homology of amino acid residues of two proteins, and additionally or alternatively with respect to the foregoing, the teachings in these references can be used for determining percent homology or identity: Needleman S B and Wunsch C D, “A general method applicable to the search for similarities in the amino acid sequences of two proteins,” J. Mol. Biol.
  • female pigs are inoculated prior to breeding; and/or prior to serving, and/or during gestation.
  • at least one inoculation is done before serving and it is preferably followed by an inoculation to be performed during gestation, e.g., at about mid-gestation (at about 6-8 weeks of gestation) and/or at the end of gestation (at about 11-13 weeks of gestation).
  • an advantageous regimen is an inoculation before mating and/o serving and a booster inoculation during gestation.
  • reinoculation before each serving and/or during gestation at about mid-gestation and/or at the end of gestation. Preferably, reinoculations are during gestation.
  • Male pigs also can be inoculated, e.g., prior to mating.
  • Piglets such as piglets from vaccinated females (e.g., inoculated as herein discussed), are inoculated within the first weeks of life, e.g., inoculation at one and/or two and/or three and/or four and/or five weeks of life.
  • piglets are first inoculated within the first week of life or within the third week of life (e.g., at the time of weaning).
  • such piglets are then boosted two to four weeks later.
  • the present invention is additionally described by the following illustrative, non-limiting Examples.
  • the invention in a preferred embodiment is directed to recombinant poxviruses containing therein a DNA sequence from PCV2 in a nonessential region of the poxvirus genome.
  • the recombinant poxviruses express gene products of the foreign PCV2 gene.
  • ORF2 and ORF1 genes encoding PCV2 proteins were isolated, characterized and inserted into ALVAC (canarypox vector) recombinants.
  • ALVAC canarypox vector
  • Imp.1010-Stoon The strain of PCV2 designated Imp.1010-Stoon has been previously described (Meehan et al., 1998). It was isolated from mesenteric lymph node tissues from a diseased pig originating from Canada. Cloning of the PCV2 genome was described by Meehan et al. (1998). Plasmid pGem7Z-Imp1010-Stoon-EcoRI No. 14 contains the PCV2 genome as an EcoRI fragment inserted into the EcoRI site of plasmid pGem-7Z (Promega, Madison, Wis.). The complete nucleotide sequence of the Imp.1010-Stoon PCV2 strain has been determined by Meehan et al. (1998) and is available under the GenBank accession number AF055392.
  • the parental canarypox virus (Rentschler strain) is a vaccinal strain for canaries.
  • the vaccine strain was obtained from a wild type isolate and attenuated through more than 200 serial passages on chick embryo fibroblasts.
  • a master viral seed was subjected to four successive plaque purifications under agar and one plaque clone was amplified through five additional passages after which the stock virus was used as the parental virus in in vitro recombination tests.
  • the plaque purified canarypox isolate is designated ALVAC.
  • ALVAC was deposited Nov. 14, 1996 under the terms of the Budapest Treaty at the American Type Culture Collection, ATCC accession number VR-2547.
  • the generation of poxvirus recombinants involves different steps: (1) construction of an insertion plasmid containing sequences (“arms”) flanking the insertion locus within the poxvirus genome, and multiple cloning site (MCS) localized between the two flanking arms (e.g., see Example 1); (2) construction of donor plasmids consisting of an insertion plasmid into the MCS of which a foreign gene expression cassette has been inserted (e.g.
  • PCV2 recombinant immunogens may be used in association with PCV1 immunogens, for immunization of animals against PMWS.
  • PCV1 immunogens may be used without PCV2 immunogens.
  • FIG. 1 is the sequence of a 3.7 kb segment of canarypox DNA. Analysis of the sequence revealed an ORF designated C6L initiated at position 377 and terminated at position 2254. The following describes a C6 insertion plasmid constructed by deleting the C6 ORF and replacing it with a multiple cloning site (MCS) flanked by transcriptional and translational termination signals.
  • MCS multiple cloning site flanked by transcriptional and translational termination signals.
  • a 380 bp PCR fragment was amplified from genomic canarypox DNA using oligonucleotide primers C6A1 (SEQ ID NO:2) and C6B1 (SEQ ID NO:3).
  • a 1155 bp PCR fragment was amplified from genomic canarypox DNA using oligonucleotide primers C6C1 (SEQ ID NO:4) and C6D1 (SEQ ID NO:5).
  • the 380 bp and 1155 bp fragments were fused together by adding them together as template and amplifying a 1613 bp PCR fragment using oligonucleotide primers C6A1 (SEQ ID NO:2) and C6D1 (SEQ ID NO:5).
  • This fragment was digested with SacI and KpnI, and ligated into pBluescript SK+ (Stratagene, La Jolla, Calif., USA) digested with SacI/KpnI.
  • the resulting plasmid, pC6L was confirmed by DNA sequence analysis. It consists of 370 bp of canarypox DNA upstream of C6 (“C6 left arm”), vaccinia early termination signal, translation stop codons in six reading frames, an MCS containing SmaI, PstI, XhoI and EcoRI sites, vaccinia early termination signal, translation stop codons in six reading frames and 1156 bp of downstream canary pox sequence (“C6 right arm”).
  • Plasmid pJP099 was derived from pC6L by ligating a cassette containing the vaccinia H6 promoter (described in Taylor et al. (1988c), Guo et al. (1989), and Perkus et al. (1989)) coupled to a foreign gene into the SmaI/EcoRI sites of pC6L.
  • This plasmid pJP099 contains a unique EcoRV site and a unique NruI site located at the 3′ end of the H6 promoter, and a unique SalI site located between the STOP codon of the foreign gene and the C6 left arm.
  • the ⁇ 4.5 kb EcoRV/SalI or NruI/SalI fragment from pJP099 contains therefore the plasmid sequence (pBluescript SK+; Stratagene, La Jolla, Calif., USA), the 2 C6 arms and the 5′ end of the H6 promoter until the EcoRV or NruI site.
  • the product of PCR J1304 was then digested with EcoRV/SalI and cloned as a ⁇ 750 bp fragment into a ⁇ 4.5 kb EcoRVISalI fragment from pJP099 (see above in Example 1).
  • the resulting plasmid was confirmed by sequence analysis and designated pJP102 (see the map of pJP102 in FIG. 2 and the sequence (SEQ ID NO:9) in FIG. 3 ).
  • the sequence of ORF 2 matches sequence available in GenBank, Accession Number AF055392.
  • the donor plasmid pJP102 (linearized with NotI) was used in an in vitro recombination (IVR) test to generate ALVAC recombinant vCP1614 (see Example 6).
  • JP760 (SEQ ID NO:7)
  • PCV2 ORF1 was amplified by PCR using primers JP774 (SEQ ID NO:9) and JP775 (SEQ ID NO:10) on plasmid pGem7Z-Imp1010-Stoon-EcoRI No. 14 resulting in PCR J1311.
  • Primer JP774 (SEQ ID NO:10) contains the 3′ end of the H6 promoter from NruI and the 5′ end of PCV2 ORF1.
  • Primer JP775 (SEQ ID NO:11) contains the 3′ end of PCV2 ORF1 followed by a SalI site.
  • the product of PCR J1311 ( ⁇ 1 Kb) was cloned into pCR2.1 (Invitrogen, Carlsbad, Calif.).
  • the resulting plasmid was confirmed by sequence analysis and designated pJP104.
  • the sequence of ORF1 matches sequence available in GenBank, Accession Number AF055392.
  • a ⁇ 970 bp NruIlSalI fragment was isolated from pJP104 and cloned into a ⁇ 4.5 kb NruI/SalI fragment from pJP099 (see Example 1), resulting in a plasmid which was confirmed by restriction analysis and designated pJP105 (see FIG. 4 ).
  • the donor plasmid pJP105 could be used in an in vitro recombination test (described in Example 6) to generate ALVAC recombinant expressing the PCV2 ORF1.
  • a ⁇ 838 bp BamHI/SalI from pJP102 was blunted using the Klenow fragment of DNA polymerase, and was cloned into the Klenow-blunted EcoRI site of pJP105. Clones were checked for orientation of insert by restriction analysis and a head-to-head orientation was chosen. This plasmid was confirmed by sequence analysis and designated pJP107 (see the map of pJP107 in FIG. 5 and the sequence (SEQ ID NO:11) in FIG. 6 ). The donor plasmid pJP107 (linearized with NotI) was used in an in vitro recombination 5 (IVR) test to generate the ALVAC recombinant vCP1615 (see Example 6).
  • IVR in vitro recombination 5
  • JP774 (SEQ ID NO:7)
  • JP775 (SEQ ID NO:12)
  • Plasmid pPCV1 (B. Meehan et al. J. Gen. Virol. 1997. 78. 221-227), containing the PCV1 genome as a PstI fragment in plasmid pGem-7Z, was used as a template to amplify the PCV1 ORF2.
  • the resulting plasmid was confirmed by sequence analysis and designated pJP113.
  • the sequence of ORF 2 matches sequence available in GenBank, Accession Number U49186.
  • the donor plasmid pJP113 (linearized with NotI) was used in an in vitro recombination (IVR) test to generate ALVAC recombinant vCP1621 (see Example 7).
  • Plasmid pPCV1 (see Example 4 above), containing the PCV1 genome as a PstI fragment in plasmid pGem-7Z, was digested with PstI, and a 1759 bp fragment was isolated and ligated.
  • Primers JP789 (SEQ ID NO:14) and JP790 (SEQ ID NO:15) were used to amplify PCV1 ORF1 from the 1759 bp ligated PstI fragment (see above), resulting in PCR J1316.
  • Primer JP789 (SEQ ID NO:14) contains the 3′ end of the H6 promoter from NruI and the 5′ end of PCV1 ORF1.
  • Primer JP790 (SEQ ID NO:15) contains the 3′ end of PCV1 ORF1 followed by a SalI site.
  • the product of PCR J1316 ( ⁇ 1 Kb) was cloned into pCR2.1 (Invitrogen, Carlsbad, Calif.).
  • the resulting plasmid was confirmed by sequence analysis and designated pJP114.
  • the sequence of ORF1 matches sequence available in GenBank, Accession Number U49186.
  • a ⁇ 970 bp NruI/SalI fragment was isolated from pJP114 and cloned into a ⁇ 4.5 kb NruI/SalI fragment from pJP099 (see Example 1), resulting in a plasmid which was confirmed by restriction analysis and designated pJP115.
  • the donor plasmid pJP115 could be used in an in vitro recombination test (described in Example 7) to generate ALVAC recombinant expressing the PCV1 ORF1.
  • a ⁇ 838 bp BamHI/SalI from pJP113 was blunted using the Klenow fragment of DNA polymerase, and was cloned into the Klenow-blunted EcoRI site of pJP115. Clones were checked for orientation of insert by restriction analysis and a head-to-head orientation was chosen. This plasmid was confirmed by sequence analysis and designated pJP117. The donor plasmid pJP117 (linearized with NotI) was used in an in vitro recombination (IVR) test to generate the ALVAC recombinant vCP1622 (see Example 7).
  • IVR in vitro recombination
  • Plasmids pJP102 (see Example 2 and FIG. 2) and pJP107 (see Example 3 and FIG. 5) were linearized with NotI and transfected into ALVAC infected primary CEF cells by using the calcium phosphate precipitation method previously described (Panicali and Paoletti, 1982; Piccini et al., 1987). Positive plaques were selected on the basis of hybridization to specific PCV2 radiolabeled probes and subjected to four sequential rounds of plaque purification until a pure population was achieved. One representative plaque from each IVR was then amplified and the resulting ALVAC recombinants were designated vCP1614 and vCP1615.
  • the vCP1614 virus is the result of recombination events between ALVAC and the donor plasmid pJP102, and it contains the PCV2 ORF2 inserted into the ALVAC C6 locus.
  • the vCP1615 virus is the result of recombination events between ALVAC and the donor plasmid pJP107, and it contains the PCV2 ORF2 and ORF1 inserted into the ALVAC C6 locus in a head-to-head orientation.
  • a recombinant ALVAC expressing only PCV2 ORF1 can be generated using the donor plasmid pJP105 described in Example 3.
  • Immunofluorescence In order to determine if the PCV2 proteins were expressed in ALVAC recombinant infected Vero cells, immunofluorescence (IF) analysis was performed. Infected Vero cells were washed with PBS 24 hrs after infection (m.o.i. of approx. 10) and fixed with 95% cold aceton for 3 minutes at room temperature. Five monoclonal antibody (MAb) preparations (hybridoma supernatant) specific for PCV2 ORF1 (PCV2 199 1D3GA & PCV2 210 7G5GD) or ORF2 (PCV2 190 4C7CF, PCV2 190 2B1BC & PCV2 190 3A8BC) were used as the first antibody.
  • MAb monoclonal antibody
  • Monoclonal antibodies were obtained from Merial-Lyon. Monoclonal antibodies can also be obtained following the teachings of documents cited herein, e.g. WO-A-99 18214, 1998, French applications Nos. 97/12382, 98/00873, 98/03707, filed Oct. 3, 1997, Jan. 22, 1998, and Mar. 20, 1998, and WO99/29717, incorporated herein by reference. The IF reaction was performed as described by Taylor et al. (1990).
  • PCV2 specific immunofluorescence with the three ORF2-specific antibodies could be detected in cells infected with vCP1614 and cells infected with vCP1615.
  • PCV2 specific immunofluorescence with the two ORF1 -specific antibodies could be detected in cells infected with vCP1615 only.
  • Plasmids pJP113 (see Example 4) and pJP117 (see Example 5) were linearized with NotI and transfected into ALVAC infected primary CEF cells by using the calcium phosphate precipitation method previously described (Panicali and Paoletti, 1982; Piccini et al., 1987). Positive plaques were selected on the basis of hybridization to specific PCV1 radiolabeled probes and subjected to four sequential rounds of plaque purification until a pure population was achieved. One representative plaque from each IVR was then amplified and the resulting ALVAC recombinants were designated vCP1621 and vCP1622.
  • the vCP1621 virus is the result of recombination events between ALVAC and the donor plasmid pJP113, and it contains the PCV1 ORF2 inserted into the ALVAC C6 locus.
  • the vCP1622 virus is the result of recombination events between ALVAC and the donor plasmid pJP117, and it contains the PCV1 ORF2 and ORF1 inserted into the ALVAC C6 locus in a head-to-head orientation.
  • a recombinant ALVAC expressing only PCV1 ORF1 can be generated using the donor plasmid pJP115 described in Example 5.
  • Immunofluorescence In order to determine if the PCV1 proteins were expressed in ALVAC recombinant infected Vero cells, immunofluorescence (IF) analysis was performed. Infected Vero cells were washed with PBS 24 hrs after infection (m.o.i. of approx. 10) and fixed with 95% cold aceton efor 3 minutes at room temperature. A specific anti-PCV1 pig polyclonal serum (Allan G. et al. Vet. Microbiol. 1999. 66: 115-123) was used as the first antibody. The IF reaction was performed as described by Taylor et al. (1990).
  • PCV1 specific immunofluorescence could be detected in cells infected with vCP1621 and cells infected with vCP1622. These results indicated that, as expected, vCP1621 and vCP1622 express PCV1-specific products. No fluorescence was detected with a PCV2-specific pig polyclonal serum in cells infected with vCP1621 and in cells infected with vCP1622. No fluorescence was detected in parental ALVAC infected Vero cells, nor in uninfected Vero cells.
  • recombinant canarypox viruses vCP1614 and vCP1615 can be mixed with solutions of carbomer.
  • recombinant canarypox viruses vCP1621 and vCP1622 can be mixed with solutions of carbomer.
  • the carbomer component used for vaccination of pigs according to the present invention is the CarbopolTM 974P manufactured by the company BF Goodrich (molecular weight of # 3,000,000).
  • a 1.5 % CarbopolTM 974P stock solution is first prepared in distilled water containing 1 g/l of sodium chloride.
  • This stock solution is then used for manufacturing a 4 mg/ml CarbopolTM 974P solution in physiological water.
  • the stock solution is mixed with the required volume of physiological water, either in one step or in several successive steps, adjusting the pH value at each step with a 1N (or more concentrated) sodium hydroxide solution to get a final pH value of 7.3-7.4.
  • This final CarbopolTM 974P solution is a ready-to-use solution for reconstituting a lyophilized recombinant virus or for diluting a concentrated recombinant virus stock.
  • Vaccine viral suspensions are prepared by dilution of recombinant viruses stocks in sterile physiological water (NaCl 0.9 %). Suitable ranges for viral suspensions can be determined empiracally, but will generally range from 10 6 to 10 10 , and preferably about 10 10 , pfu/dose. Vaccine solutions can also be prepared by mixing the recombinant virus suspension with a solution of CarbopolTM 974P, as described in Example 8.
  • Piglets are vaccinated either with:
  • Recombinant virus vCP1614 mixed with Carbopol (4 mg/ml solution); or
  • Recombinant virus vCP1615 mixed with Carbopol (4 mg/ml solution).
  • the viral suspensions contain 10 8 plaque forming units (pfu) per dose. Each viral suspension is injected by intramuscular route under a volume of 1 ml. The intramuscular injection is administered into the muscles of the neck.
  • Two injections of viral suspensions are administered at Day 2 and Day 14 of the experiment.
  • a challenge is done on Day 21 by an oronasal administration of a viral suspension prepared from a culture of PCV-2 virulent strain.
  • piglets are monitored during 3 weeks for clinical signs specific of the post-weaning multisystemic syndrome. The following signs are scored:
  • Rectal temperature daily monitoring for 2 weeks post-challenge, then 2 measures of rectal temperature during the third week.
  • Weight piglets are weighed right before the challenge, and then weekly during the first 3 weeks post-challenge.
  • Blood samples are taken at Day 2, day 14, Day 21, Day 28, Day 35 and Day 42 of the experiment in order to monitor viremia levels and anti-PCV-2 specific antibody titers.
  • Necropsies at Day 42, all surviving piglets are humanely euthanized and necropsied to look for specific PWMS macroscopic lesions. Tissue samples are prepared from liver, lymph nodes, spleen, kidneys and thymus in order to look for specific histological lesions.
  • Vaccine viral suspensions are prepared by dilution of recombinant viruses stocks in sterile physiological water (NaCl 0.9%).
  • Vaccine solutions can also be prepared by mixing the recombinant virus suspension with a solution of CarbopolTM 974P, as described in Example 8.
  • Piglets are vaccinated either with:
  • Recombinant virus vCP1614 mixed with Carbopol (4 mg/ml solution); or
  • Recombinant virus vCP1615 mixed with Carbopol (4 mg/ml solution).
  • the viral suspensions contain 10 8 plaque forming units (pfu) per dose.
  • Each viral suspension is injected by intramuscular route under a volume of 2 ml. The intramuscular injection is administered into the muscles of the neck. Two injections of the viral suspensions are administered at Day 0 and Day 21 of the experiment.
  • a challenge is done at Day 35 by an oronasal administration of a viral suspension prepared from a culture of PCV-2 virulent strain.
  • piglets are monitored during 8 weeks for clinical signs specific of the post-weaning multisystemic syndrome. The clinical monitoring is identical to the one described in Example 9.1. except that total duration of monitoring is 8 weeks instead of 3 weeks.
  • Necropsies are done throughout the experiment for piglets dying from the challenge and at the end of the experiment (Day 97) for all surviving piglets. Tissue samples are the same as described in Example 9.1.
  • Day 2 the piglets are vaccinated with 10 8 pfu of vCP1614, vCP1615 or parental ALVAC vector in 1 ml of PBS by intramuscular route on the side of the neck.
  • a second injection of vaccine or placebo is administered at day 14.
  • Vaccination with ALVAC recombinant is well tolerated by piglets and no evidence of adverse reaction to vaccination is noted.
  • the piglets are challenged day 21 by oronasal administration of a PCV-2 viral suspension, 1 ml in each nostril. Day 45 necropsies are performed and samples of tissues are collected for virus isolation. Necropsy results:
  • Bronchial lymphadenopathy for PCV-2 is a prominent gross finding. A significant reduction of the lymph nodes lesion in relation to control group is observed after immunization with vCP 1614 and vCP1615 (p ⁇ 0.05).

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US09/583,545 US6497883B1 (en) 1999-06-10 2000-06-01 Porcine circovirus recombinant poxvirus vaccine
AU54189/00A AU778520B2 (en) 1999-06-10 2000-06-09 Porcine circovirus recombinant poxvirus vaccine
DK00938971.9T DK1185660T3 (da) 1999-06-10 2000-06-09 Svinecircovirus-vaccine i rekombinant poxvirus
ES08005549.4T ES2560513T3 (es) 1999-06-10 2000-06-09 Vacuna de poxvirus recombinante contra el circovirus porcino
DE60044778T DE60044778D1 (de) 1999-06-10 2000-06-09 Schweine-circovirus-impfstoff in rekombinantem pockenvirus
CA2376600A CA2376600C (fr) 1999-06-10 2000-06-09 Vaccin poxvirus recombine contre le circovirus porcin
PL352201A PL205032B1 (pl) 1999-06-10 2000-06-09 Immunogenna kompozycja obejmująca rekombinowany wirus ospy obejmujący wyizolowaną cząsteczkę DNA, zastosowanie rekombinowanego wirusa ospy obejmującego cząsteczkę wyizolowanego DNA oraz szczepionka
PT80055494T PT1975235E (pt) 1999-06-10 2000-06-09 Vacina de poxvírus recombinante contra o circovírus porcino
DK08005549.4T DK1975235T3 (en) 1999-06-10 2000-06-09 Porcine circovirus vaccine in recombinant poxvirus
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HU0201689A HU229051B1 (en) 1999-06-10 2000-06-09 Porcine circovirus vaccine in reconbinant poxvirus
EP08005549.4A EP1975235B1 (fr) 1999-06-10 2000-06-09 Vaccin contre le poxvirus recombinant cirovirus porcin
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HUP0201689A2 (en) 2002-09-28
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